Sun et al.
(2R,8R,11S)-2-(3-chlorophenyl)-8-methyl-11-(1-methylethyl)-1,5-di-
oxaspiro[5.5]undecane: 1H NMR (CDCl3, 600 MHz) d: 7.36 (s, 1H),
7.30–7.22 (m, 3H), 5.03 (d, J 12 Hz, 1H), 4.02 (t, J 12 Hz, 1H), 3.86
(dd, J1 4.2, J2 11.4 Hz, 1H), 2.82 (d, J 13.2 Hz, 1H), 2.58 (m, 1H),
1.84–1.72 (m, 2H), 1.62 (d, J 13.2 Hz, 1H), 1.59–1.54 (m, 2H), 1.50–
1.42 (m, 1H), 1.34 (d, J 12.6 Hz, 1H), 0.98–0.95 (t, J 6 Hz, 6H), 0.93
(d, J 6.6 Hz, 3H), 0.90 (d, J 9.6 Hz, 1H), 0.81 (t, J 13.2 Hz, 1H). ESI-
MS m ⁄ z: 323.2[M+H]+.
cis-3-O-[4-(R)-(3-Chlorophenyl)-2-oxo-1,3,2-
dioxaphosphorinan-2-yl]-18b-glycyrrhetinic acid
(5R) and cis-3-O-[4-(S)-(3-Chlorophenyl)-2-oxo-
1,3,2-dioxaphosphorinan-2-yl]-18b-
glycyrrhetinic acid (5S)
A solution of 18b-glycyrrhetinic acid (1.26 g, 2.68 mmol) in THF
(30 mL) was treated with a THF solution of 2 M lithium diisopro-
pylamide (LDA) (6.7 mL, 13.4 mmol) and stirred at room tempera-
ture. After 2 h, 4R or 4S (1.5 g, 4.06 mmol) was added in one
portion. The mixture was stirred at room temperature for 48 h and
quenched with saturated NH4Cl. Then THF was removed in vacuo.
1 M HCl was dropped to the mixture at 0 ꢀC until pH <3. The mix-
ture was extracted with CH2Cl2. The organic layer was dried and
concentrated. The residue was purified by chromatography to obtain
0.89 g (47.3%) of 5R or 0.88 g (46.8%) of 5S.
(2S,8R,11S)-2-(3-chlorophenyl)-8-methyl-11-(1-methylethyl)-1,5-di-
oxaspiro[5.5]undecane: 1H NMR (CDCl3, 600 MHz) d: 7.36 (s, 1H),
7.29–7.22 (m, 3H), 4.85 (d, J 11.4 Hz, 1H), 4.25 (t, J 12 Hz, 1H),
3.91 (dd, J1 4.8, J2 11.4 Hz, 1H), 2.83 (d, J 12.6 Hz, 1H), 2.50 (m,
1H), 2.05–1.90 (m, 2H), 1.85–1.81 (m, 1H), 1.73–1.67 (m, 2H), 1.55–
1.53 (m, 1H), 1.52–1.49 (m, 1H), 1.31–1.27 (m, 1H), 0.98 (d, J
6.6 Hz, 3H), 0.95 (d, J 6.6 Hz, 3H), 0.91 (d, J 6.6 Hz, 3H), 0.80 (t, J
13.2 Hz, 1H). ESI-MS m ⁄ z: 323.1[M+H]+.
5R: mp>200 ꢀC; [a]D +102.4ꢀ (c 2.9, CHCl3); 1H NMR (CDCl3,
600 MHz) d: 7.41–7.25 (m, 4H, Ar-H), 5.69 (s, 1H, 12-H), 5.38 (dd,
1H, J1 1.2, J2 11.4 Hz, 4¢-H), 4.53–4.40 (m, 2H, 6¢-H), 4.26–4.21 (m,
1H, 3-H), 2.29–2.23 (m, 2H, 5¢-H), 1.36 (s, 3H, 27-H), 1.21 (s, 3H,
29-H), 1.16 (s, 3H, 25-H), 1.12 (s, 3H, 23-H), 1.08 (s, 3H, 26-H), 0.92
(s, 3H, 24-H), 0.82 (s, 3H, 28-H); 13C NMR (CDCl3, 150 MHz) d:
200.1 (11-C), 181.2 (30-C), 169.7 (13-C), 140.9 (1¢¢-C), 134.8 (3¢¢-C),
130.1 (5¢¢-C), 128.8 (2¢¢-C), 128.4 (12-C), 125.7 (6¢¢-C), 123.6 (4¢¢-C),
86.7 (3-C), 79.8 (4¢-C), 67.6 (6¢-C), 61.6 (9-C), 54.9 (5-C), 48.2 (18-C),
45.4 (14-C), 43.8 (20-C), 43.2 (8-C), 40.9 (5¢-C), 39.1 (4-C), 39.1 (1-C),
38.6 (19-C), 37.7 (22-C), 36.7 (10-C), 34.0 (2-C), 32.7 (17-C), 31.9 (7-
C), 30.9 (16-C), 28.5 (21-C), 28.4 (29-C), 28.1 (23-C), 26.5 (15-C), 26.4
(27-C), 25.2 (24-C), 23.4 (28-C), 18.7 (25-C), 17.5 (6-C), 16.4 (26-C).
31P NMR (CDCl3, 243MHz) d: )7.40. ESI-MS m ⁄ z: 701.5[M+H]+;
HRMS (ESI): calcd for C39H54ClO7PNa: 723.3228 found 723.3193.
A concentrated hydrochloric acid of 8 mL was added to a solution of
(2R,8R,11S)-2-(3-chlorophenyl)-8-methyl-11-(1-methylethyl)-1,5-di-
oxaspiro[5.5]undecane or (2S,8R,11S)-2-(3-chlorophenyl)-8-methyl-11-
(1-methylethyl)-1,5-dioxaspiro[5.5]undecane (10.5 g, 32.6 mmol) in
MeOH (70 mL) at room temperature. The mixture was stirred for
10–20 h. Water was then added. MeOH was removed in vacuo.
The mixture was extracted three times with ethyl acetate. The
combined extracts were dried and concentrated. The residue was
purified by chromatography with petroleum ether ⁄ ethyl acetate to
obtain the optically active diol 5.04 g (82.8%) of 3R or 4.78 g
(69.3%) of 3S. 3R: [a]D +54.3ꢀ (c 0.96, CHCl3). 3S: [a]D )50.8ꢀ
(c 0.90, CHCl3).
(4R)-(+)-trans-2-(4-nitrophenoxy)-2-oxido-(3-
chlorophenyl)-1,3,2-dioxaphosphorinane (4R)
and (4S)-())-trans-2-(4-nitrophenoxy)-2-oxido-(3-
chlorophenyl)-1,3,2-dioxaphosphorinane (4S)
A solution of 3R or 3S (3.89 g, 20.8 mmol) and Et3N (10.7 mL,
77.5 mmol) in THF (50 mL) was added dropwise to a solution of 4-
nitrophenoxyphosphorodichloridate (9.9 g, 38.7 mmol) in THF (8 mL)
at 0 ꢀC. The starting diol was consumed in 2 h. Additional Et3N
(10.7 mL, 77.5 mmol) and 4-nitrophenol (9.9 g, 38.7 mmol) were
added. The mixture was stirred overnight. After the solvent was
evaporated, the residue was taken up in ethyl acetate, washed with
water, 0.4 M NaOH, and brine. It was dried and concentrated. The
residue was purified by chromatography with petroleum ether ⁄ ethyl
acetate to give 4.8 g (62.3%) of 4R or 5.4 g (78.3%) of 4S.
5S: mp>200 ꢀC; [a]D +55.3ꢀ (c 2.9, CHCl3); 1H NMR (CDCl3,
600 MHz) d: 7.41–7.26 (m, 4H, Ar-H), 5.71 (s, 1H, 12-H), 5.42 (dd,
1H, J1 1.8, J2 11.4 Hz, 4¢-H), 4.51–4.38 (m, 2H, 6¢-H), 4.27–4.22 (m,
1H, 3-H), 2.29–2.18 (m, 2H, 5¢-H), 1.36 (s, 3H, 27-H), 1.23 (s, 3H,
29-H), 1.18 (s, 3H, 25-H), 1.13 (s, 3H, 23-H), 1.05 (s, 3H, 26-H), 0.90
(s, 3H, 24-H), 0.83(s, 3H, 28-H); 13C NMR (CDCl3, 150 MHz) d: 200.2
(11-C), 181.1 (30-C), 169.7 (13-C), 141.2 (1¢¢-C), 134.7 (3¢¢-C), 130.0
(5¢¢-C), 128.7 (2¢¢-C), 128.4 (12-C), 125.7 (6¢¢-C), 123.5 (4¢¢-C), 86.6
(3-C), 80.1 (4¢-C), 67.2 (6¢-C), 61.6 (9-C), 54.9 (5-C), 48.2 (18-C), 45.4
(14-C), 43.8 (20-C), 43.2 (8-C), 40.9 (5¢-C), 39.1 (4-C), 39.0 (1-C), 38.7
(19-C), 37.7 (22-C), 36.7 (10-C), 34.1 (2-C), 32.7 (17-C), 31.9 (7-C),
30.9 (16-C), 28.5 (21-C), 28.4 (29-C), 28.1 (23-C), 26.5 (15-C), 26.4
(27-C), 25.2 (24-C), 23.3 (28-C), 18.7 (25-C), 17.5 (6-C), 16.4 (26-C).
31P NMR (CDCl3, 243 MHz) d: )7.16. ESI-MS m ⁄ z: 701.4[M+H]+;
HRMS (ESI): calcd for C39H54ClO7PNa: 723.3212 found 723.3193.
1
4R: mp 113–116 ꢀC; [a]D +90.1ꢀ (c 1.00, CHCl3); H NMR (CDCl3,
600 MHz) d: 8.26 (d, J 8.4 Hz, 2H), 7.45 (d, J 8.4 Hz, 2H), 7.41 (s,
1H), 7.37–7.34 (m, 2H), 7.30–7.28 (m, 1H), 5.57 (dd, J1 1.8, J2
12 Hz, 1H), 4.67–4.56 (m, 2H), 2.45–2.37 (m, 1H), 2.13–2.09 (m, 1H).
ESI-MS m ⁄ z: 370.1[M+H]+.
Biology
Aqueous solubility
To increase the aqueous solubility of 5R and 5S, PGAs were con-
verted to the relevant sodium salts (PGAs-Na) by the reactions with
sodium hydroxide in ethanol. Solubility of PGAs-Na was measured
by dissolving prodrug of 5 mg ⁄ mL in PBS at pH 7.4. Samples were
then sonicated for 5 min in a sonication bath and stayed at room
temperature for 10 min. After filtration with 0.45 lm micro-pore fil-
ter membrane, the samples were diluted 1: 100 in DMSO and anal-
1
4S: mp 112–115 ꢀC; [a]D )90.8ꢀ (c 1.30, CHCl3); H NMR (CDCl3,
600 MHz) d: 8.25 (d, J 9 Hz, 2H), 7.45 (d, J 9.6 Hz, 2H), 7.41 (s,
1H), 7.37–7.35 (m, 2H), 7.29–7.26 (m, 1H), 5.57 (dd, J1 2.4, J2
12 Hz, 1H), 4.67–4.55 (m, 2H), 2.45–2.36 (m, 1H), 2.13–2.09 (m, 1H).
ESI-MS m ⁄ z: 370.1[M+H]+.
208
Chem Biol Drug Des 2011; 77: 206–211